Lackner Angela, Cabral Julia Elise, Qiu Yanfei, Zhou Haitian, Leonidas Lemuel, Pham Minh Anh, Macapagal Alijah, Lin Sophia, Armanus Emy, McNulty Reginald
Laboratory of Macromolecular Structure, Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA.
Department of Pharmaceutical Sciences, University of California, Irvine, Steinhaus Hall, Irvine, CA 92694-3900, USA.
iScience. 2024 Jul 5;27(8):110459. doi: 10.1016/j.isci.2024.110459. eCollection 2024 Aug 16.
Despite recent advances in the mechanism of oxidized DNA activating NLRP3, the molecular mechanism and consequence of oxidized DNA associating with NLRP3 remains unknown. Cytosolic NLRP3 binds oxidized DNA which has been released from the mitochondria, which subsequently triggers inflammasome activation. Human glycosylase (hOGG1) repairs oxidized DNA damage which inhibits inflammasome activation. The fold of NLRP3 pyrin domain contains amino acids and a protein fold similar to hOGG1. Amino acids that enable hOGG1 to bind and cleave oxidized DNA are conserved in NLRP3. We found NLRP3 could bind and cleave oxidized guanine within mitochondrial DNA. The binding of oxidized DNA to NLRP3 was prevented by small molecule drugs which also inhibit hOGG1. These same drugs also inhibited inflammasome activation. Elucidating this mechanism will enable the design of drug memetics that treat inflammasome pathologies, illustrated herein by NLRP3 pyrin domain inhibitors which suppressed interleukin-1β (IL-1β) production in macrophages.
尽管近期在氧化型DNA激活NLRP3的机制方面取得了进展，但氧化型DNA与NLRP3结合的分子机制和后果仍不清楚。胞质中的NLRP3与从线粒体释放的氧化型DNA结合，随后触发炎性小体激活。人类糖基化酶（hOGG1）修复氧化型DNA损伤，从而抑制炎性小体激活。NLRP3吡啉结构域的折叠包含与hOGG1相似的氨基酸和蛋白质折叠。使hOGG1能够结合并切割氧化型DNA的氨基酸在NLRP3中是保守的。我们发现NLRP3能够结合并切割线粒体DNA中的氧化鸟嘌呤。氧化型DNA与NLRP3的结合可被同样抑制hOGG1的小分子药物阻断。这些相同的药物也抑制炎性小体激活。阐明这一机制将有助于设计治疗炎性小体相关疾病的药物模拟物，本文以抑制巨噬细胞中白细胞介素-1β（IL-1β）产生的NLRP3吡啉结构域抑制剂为例进行说明。
